Nutritional supplement for increasing cognitive functions

ABSTRACT

The invention provides compositions and methods that are effective to improve NO production in vivo and/or to increase NO levels in blood. Such compositions and methods are useful to increase oxygenation of the brain and to improve cognitive function.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 15/829,801 filed on Dec. 1, 2017. The entire content of theapplication referenced above is hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

Nitric Oxide Synthase (NOS) in endothelial cells converts L-arginine toL-hydroxyarginine and subsequently to nitric oxide (NO) and L-citrulline(FIG. 1 and FIG. 2). NO exherts its biological action on smooth muscleby increasing cGMP, which leads to vasodialation and increased bloodflow in the brain. Two L-citrulline molecules combine to generateL-arginine to boost the NO generation cycle. NO acts as aneurotransmitter for the autonomic nervous system, increases cerebralblood flow and oxygenation of the brain, and improves cognitivefunctions.

A previous dietary supplement was designed and sold to maximize thebenefits of NO. It contained the amino acids L-citruline and L-arginine,as well as BioPerine® (extract, FIG. 3) that helps the body absorb theamino acids (see U.S. Pat. No. 5,536,506 and European PatentEP0810868B1). BioPerine® (extract) inhibits human CYP3A4 andP-glycoprotein enzymes. By inhibiting certain enzymes BioPerine®(extract) may alter the effectiveness of certain medications byincreasing bioavailability. The active ingredients in this previousdiatary supplement were the amino acids L-citruline and L-arginine,which served as a substrate for NO generation. The previous diatarysupplement was sold and administered as a capsule containing 500 mg ofL-citrulline, 250 mg of L-arginine, and 1.5 mg of bioperine. Therecommended dosage was two capsules per day. In spite of the successrealized with the previous diatary supplement, there remains a need foradditional formulations that provide improved effects.

SUMMARY OF THE INVENTION

Applicant has determined that the beneficial effects of the previousdiatary supplement can be significantly improved by increasing theamount of piperine in the formulation from 1.5 mg to about 5 mg. Basedon the suggested administration of two capsules per day, this representsan increase in the amount of piperine from 3.0 mg to about 10.0 mg perday.

Accordingly, in one embodiment the invention provides a unit dosage formsuitable for oral administration to a human comprising: L-citrulline(500 mg±20 mg); L-arginine (250 mg ±20 mg); and at least about 5 mgpiperine.

In another embodiment the invention provides a unit dosage form suitablefor oral administration to a human comprising: about 500 mg ofL-citrulline; about 250 mg of L-arginine; and about 5 mg of bioperine.

In another embodiment the invention provides a method to increase NOlevels in the blood of a mammal comprising administering a unit dosageform of the invention to the mammal.

In another embodiment the invention provides a method to increasecerebral blood flow in a mammal comprising administering a unit dosageform of the invention to the mammal.

In another embodiment the invention provides a method to increaseoxygenation of the brain in a mammal comprising administering a unitdosage form of the invention to the mammal.

In another embodiment the invention provides a method to improvecognitive function in a mammal comprising administering a unit dosageform of the invention to the mammal.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 shows the conversion of L-citrulline and L-argenine to NO.

FIG. 2 shows how Nitric Oxide Synthase (NOS) in endothelial cellsconverts L-arginine to L-hydroxyarginine and subsequently to nitricoxide (NO) and L-citrulline.

FIG. 3 shows the structure for piperine.

DETAILED DESCRIPTION

As used herein, the term “about” has its generally accepted meaning. Inone embodiment, the term about means±10% of the associated value. Forexample, about 100 mg means 100 mg±10 mg. In one embodiment, the termabout means±5% of the associated value. For example, about 100 mg means100 mg±5 mg. In one embodiment, the term about means±2% of theassociated value. For example, about 100 mg means 100 mg±2 mg. In oneembodiment, the term about means±1% of the associated value. Forexample, about 100 mg means 100 mg±1 mg.

In one embodiment a unit dosage form of the invention may contain one ormore pharmaceutical diluents or excipients. For example, in oneembodiment a unit dosage form of the invention may comprisemicrocrystalline cellulose, silicon dioxide, and magnesium stearate.

In one embodiment a unit dosage form of the invention may comprise atleast about 480 mg of L-citrulline.

In one embodiment a unit dosage form of the invention may comprise atleast about 490 mg of L-citrulline.

In one embodiment a unit dosage form of the invention may comprise atleast about 500 mg of L-citrulline.

In one embodiment a unit dosage form of the invention may comprise atleast about 230 mg of L-arginine.

In one embodiment a unit dosage form of the invention may comprise atleast about 240 mg of L-arginine.

In one embodiment a unit dosage form of the invention may comprise atleast about 250 mg of L-arginine.

In one embodiment the piperine is synthetically produced piperine.

In one embodiment the piperine is an extract from the fruit of Piper.

L-Argenine is an α-amino acid that is used in the biosynthesis ofproteins. It is the precursor for the biosynthesis of nitric oxide.L-Argenine has the following structure:

In humans, arginine is classified as a semiessential or conditionallyessential amino acid, depending on the developmental stage and healthstatus of the individual. L-Argenine is commercially available from avariety of sources.

L-Citrulline is an a-amino acid that is a key intermediate in the ureacycle, the pathway by which mammals excrete ammonia by converting itinto urea. Citrulline is also produced as a byproduct of the enzymaticproduction of nitric oxide from the amino acid arginine, catalyzed bynitric oxide synthase. L-Citrulline has the following structure:

L-Citrulline is commercially available from a variety of sources.

Bioperine® is a patented absorption enhancer, obtained from black pepperfruits (Piper nigrum). Bioperine® helps the body absorb the amino acids(see U.S. Pat. No. 5,536,506 and European Patent EP0810868B1).Bioperine® (extract) inhibits human CYP3A4 and P-glycoprotein enzymes.By inhibiting certain enzymes Bioperine® (extract) may alter theeffectiveness of certain medications by increasing bioavailability.Bioperine is Generally Recognized As Safe (GRAS). Bioperine® (CAS Reg.No. 94-62-2) is named as 1-piperylpiperidine;5-(1,3-benzodioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one; and(2E,4E)-5-(1,3-benzodioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one,and has the structure:

1-Piperylpiperidine is commercially available from a variety of sources.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLE 1.

The chart below describes the changes between the old formulation andthe present invention based on the satisfaction rate for the customer'sprocessing fees. The new formulation shows a 19.9 percent increaseprocessing speed over four months as opposed to the old formulation withonly as 2.9 percent increase in processing speed.

Old Formulation Present Invention Satisfaction Rate Satisfaction RateBaseline 688 59 At 4 Month 62.3 78.9 % Increase 2.9 19.9

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1-19. (canceled)
 20. A method to increase NO levels in the blood of amammal comprising administering two unit dosage forms a day to themammal, wherein each unit dosage form comprises: L-citrulline 500 mg±20mg; L-arginine 250 mg±20 mg; and at least about 5 mg piperine.
 21. Themethod of claim 20 wherein each unit dosage form comprises at leastabout 5.5 mg piperine.
 22. The method of claim 20 wherein each unitdosage form comprises at least about 480 mg of L-citrulline.
 23. Themethod of claim 20 wherein each unit dosage form comprises at leastabout 230 mg of L-arginine.
 24. The method of claim 20 wherein each unitdosage form further comprises microcrystalline cellulose, silicondioxide, and magnesium sterate.
 25. The method of claim 20 wherein eachunit dosage form is formulated as a capsule, powder, or liquid.
 26. Amethod to increase oxygenation of the brain in a mammal comprisingadministering two unit dosage forms a day to the mammal, wherein eachunit dosage form comprises: L-citrulline 500 mg±20 mg; L-arginine 250mg±20 mg; and at least about 5 mg piperine.
 27. The method of claim 26wherein each unit dosage form comprises at least about 5.5 mg piperine.28. The method of claim 26 wherein each unit dosage form comprises atleast about 480 mg of L-citrulline.
 29. The method of claim 26 whereineach unit dosage form comprises at least about 230 mg of L-arginine. 30.The method of claim 26 wherein each unit dosage form further comprisesmicrocrystalline cellulose, silicon dioxide, and magnesium sterate. 31.The method of claim 26 wherein each unit dosage form is formulated as acapsule, powder, or liquid.
 32. A method to improve cognitive functionin a mammal comprising administering two unit dosage forms a day to themammal, wherein each unit dosage form comprises: L-citrulline 500 mg±20mg; L-arginine 250 mg±20 mg; and at least about 5 mg piperine.
 33. Themethod of claim 32 wherein each unit dosage form comprises at leastabout 5.5 mg piperine.
 34. The method of claim 32 wherein each unitdosage form comprises at least about 480 mg of L-citrulline.
 35. Themethod of claim 32 wherein each unit dosage form comprises at leastabout 230 mg of L-arginine.
 36. The method of claim 32 wherein each unitdosage form further comprises microcrystalline cellulose, silicondioxide, and magnesium sterate.
 37. The method of claim 32 wherein eachunit dosage form is formulated as a capsule, powder, or liquid.